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Biological and Cognitive Markers of Presenilin1 E280A Autosomal Dominant Alzheimer's Disease: A Comprehensive Review of the Colombian Kindred

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Joshua T. Fox‐Fuller, Alice Cronin‐Golomb, Jennifer R. Gatchel, D.J. Norton, Edmarie Guzmán‐Vélez, Heidi I.L. Jacobs, Bernard Jimmy Hanseeuw, Enmanuelle Pardilla‐Delgado +11 more·2019·The Journal of Prevention of Alzheimer s Disease
DOI 10.14283/jpad.2019.6PMC PMC6925534
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Abstract

The study of individuals with autosomal dominant Alzheimer's disease affords one of the best opportunities to characterize the biological and cognitive changes of Alzheimer's disease that occur over the course of the preclinical and symptomatic stages. Unifying the knowledge gained from the past three decades of research in the world's largest single-mutation autosomal dominant Alzheimer's disease kindred - a family in Antioquia, Colombia with the E280A mutation in the Presenilin1 gene - will provide new directions for Alzheimer's research and a framework for generalizing the findings from this cohort to the more common sporadic form of Alzheimer's disease. As this specific mutation is virtually 100% penetrant for the development of the disease by midlife, we use a previously defined median age of onset for mild cognitive impairment for this cohort to examine the trajectory of the biological and cognitive markers of the disease as a function of the carriers' estimated years to clinical onset. Studies from this cohort suggest that structural and functional brain abnormalities - such as cortical thinning and hyperactivation in memory networks - as well as differences in biofluid and in vivo measurements of Alzheimer's-related pathological proteins distinguish Presenilin1 E280A mutation carriers from non-carriers as early as childhood, or approximately three decades before the median age of onset of clinical symptoms. We conclude our review with discussion on future directions for Alzheimer's disease research, with specific emphasis on ways to design studies that compare the generalizability of research in autosomal dominant Alzheimer's disease to the larger sporadic Alzheimer's disease population.

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  • Classical biomarkers such as cerebrospinal fluid and plasma define disease staging decades before onset but mainly reflect downstream protein pathology.

    “Classical biomarkers such as cerebrospinal fluid (CSF) and plasma define disease staging decades before onset but mainly reflect downstream protein pathology. 42”

    From Plasma extracellular vesicles from <i>APOE3</i> Christchurch carriers display a protective phenotype in early stages of autosomal dominant Alzheimer's disease (2026) · cites this paper as [42]

    The Results section (‘Plasma, CSF, and other in vivo markers of AD pathology’; page unavailable) reports CSF and plasma amyloid abnormalities decades before symptoms in PSEN1 E280A carriers. The Discussion describes a suggested temporal order modeled from cross-sectional findings, not definitive disease staging. The paper identifies these as markers of AD pathology but does not characterize them as mainly reflecting downstream protein pathology. (LLM, conf=0.86)

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Cited by

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Authors
Fox‐Fuller, J. T., Cronin‐Golomb, A., Gatchel, J. R., Norton, D. J., Guzmán‐Vélez, E., Jacobs, H. I. L., Hanseeuw, B. J., Pardilla‐Delgado, E., Artola, A., Baena, A. Y., Bocanegra, Y., Kosik, K. S., Chen, K., Tariot, P. N., Johnson, K., Sperling, R. A., Reiman, E. M., Lopera, F. J., & Quiroz, Y. T.
Affiliations
  • Boston University (US)
  • Harvard University (US)
  • Williams College (US)
  • Universidad de Antioquia (CO)
  • University of California, Santa Barbara (US)
  • Banner Alzheimer’s Institute (US)
  • Brigham and Women's Hospital (US)
Corresponding author
Yakeel T. Quiroz
ORCID
Venue
The Journal of Prevention of Alzheimer s Disease
Publisher
Elsevier BV
Published
2019-04
Volume
6
Issue
2
Pages
112-120
ISSN
2274-5807 (ISSN-L)
DOI
10.14283/jpad.2019.6
PMC
PMC6925534
OpenAlex
W2912429878
Cited by
57
References
7
Citations by year
2026: 6 · 2025: 7 · 2024: 3 · 2023: 9 · 2022: 5 · 2021: 16 · 2020: 9 · 2019: 1 · 2018: 1
FWCI
1.30
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Prevention of Alzheimer s Disease (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • OpenBU (Boston University) (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • Research Publications (Maastricht University) (submittedVersion, cc-by-nc-nd)
  • Digital Access to Libraries (Université catholique de Louvain (UCL), l'Université de Namur (UNamur) and the Université Saint-Louis (USL-B)) (submittedVersion, other-oa)
  • OpenBU (Boston University) (submittedVersion)
  • Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
  • Research Publications (Maastricht University) (submittedVersion)
  • Greater South Information System
Funders
  • Alzheimer's Association (AACF-16-440965, U01 AG024904)
  • Harvard NeuroDiscovery Center
  • Abbott Laboratories
  • Amgen
  • Bristol-Myers Squibb (U01 AG024904, AG024904)
  • Eli Lilly and Company (U01 AG024904, R01 AG037497, U19 AG010483, U01 AG032438, AG024904, R01 AG034556)
  • Pfizer (AG024904, U01 AG024904)
  • AstraZeneca
  • Massachusetts General Hospital (1200-228767, 1200-228010)
  • Biogen (U01 AG024904, AG024904)
  • Arizona Department of Health Services
  • Departamento Administrativo de Ciencia, Tecnología e Innovación (COLCIENCIAS) (111565741185)
  • University of Rochester
  • Cognoptix
  • GHR Foundation
  • European Commission (U01 AG024904, 706714)
  • Fonds De La Recherche Scientifique - FNRS (#SPD 28094292)
  • Eisai (U01 AG024904, AG024904)
  • NOMIS Stiftung
  • H. Lundbeck A/S (U01 AG024904, AG024904)
  • National Institutes of Health (5u01ag024904-10, DP5OD019833, U01-AG024904, AG010483, AG024904)
  • Genentech (AG024904, U01 AG024904)
  • Fidelity Biosciences (U01 AG032438, R01 AG037497, U01 AG024904, U19 AG010483, R01 AG034556)
  • National Institute on Aging (U01-AG-024904, K23AG058805, AG 032438, RF1AG041705, AG 010483, AG 024904, R01AG055444, AG058805-01, R01AG037497, P30AG019610, R01AG054671, U19AG010483, U01AG032438, R01AG034556)
  • NIH Office of the Director (DP5 OD019833)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
autosomal dominant Alzheimer's disease, preclinical Alzheimer's disease, mild cognitive impairment, cognitive markers, biomarkers, cortical thinning, amyloid-beta, tau protein, biofluid biomarkers
MeSH terms
Mental Status and Dementia Tests, Adolescent, Adult, Alzheimer Disease, Aniline Compounds, Brain, Child, Colombia, Electroencephalography, Ethylene Glycols, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Peptide Fragments, Biomarkers, Tomography, Emission-Computed, Single-Photon, Amyloid beta-Peptides, Disease Progression, Radiopharmaceuticals, Positron-Emission Tomography, Presenilin-1, Young Adult, Diffusion Tensor Imaging, Asymptomatic Diseases, Functional Neuroimaging

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